prise en charge des lymphomes de hodgkin avancés...
TRANSCRIPT
Prise en charge des lymphomes de Hodgkin avancés
O. Casasnovas
Hématologie Clinique
CHU Dijon, France
Stratification EORTC/GELA GHSG
Médiastin/Thorax > 0.35
4 aires ganglionnaires
B et VS 30
ou A et VS 50
Age 50
Médiastin/Thorax > 0.33
3 aires ganglionnaires
B et VS 30
ou A et VS 50
Atteinte extra-nodale
Aucun facteur: Favorable Facteur 1+: Défavorable
Aucun facteur: Favorable Facteur 1+: Intermédiaire
Exclus: Stades IIB [M/T>0.33, AEN]
Stades I -II
Stades III -IV LH avancé + Stades IIB [M/T>0.33, AEN]
LH avancé
Long-Term Follow-up
Advanced HL: stages IIB-LMM, III, IV
Failure-free survival Overall survival
Years after study entry
Canellos et al. NEJM, 2002
HL : Chemotherapy
ABVD regimen Dose D1 D15
Doxorubicin 25 mg/m2 (IV) X X
Bleomycin 10 mg/m2 (IV) X X
Vinblastine 6 mg/m2 (IV) X X
Dacarbazine 375 mg/m2 (IV) X X
BEACOPPesc
regimen Dose D1 D2 D3 D4 D5 D6 D7 D8
D9 to D14
Bleomycin 10 mg/m2 (IV) X Etoposide 200 mg/m2 (IV) X X X
Doxorubicin 35 mg/m2 (IV) X Cyclophosphamide 1250 mg/m2 (IV) X
Vincristine 1,4 mg/m2 (IV) [2mg max] X Procarbazine 100 mg/m2 (PO) X X X X X X X Prednisone 40 mg/m2(PO) X X X X X X X X X
1973
1993
ABVD • Contrôle de la maladie insuffisant pour 25 à 30 % des pts
• Toxicité – Pulmonaire
• Mayo clinic (n = 141): 18% des patients • MSKCC (n = 152): 22% d’arret précoce de la bleomycine • Hoskin et al (UK) : 10% de toxicité pulmonaire g>3 • RATHL: Réduction de DLCO moyenne = 11% après 6 ABVD
= 4.3% après 2 ABVD + 4 AVD
n CR 5y-PFS Follow-up
Gordon JCO 2013 404 73% 74% 77 months
Chisesi JCO 2011 126 89% 78% 86 months
Viviani NEJM 2011 166 76% 73% 61 months
Federico JCO 2009 102 84% 68% 41 months
Hoskin JCO 2009 261 67% 76% 52 months
CS IIB-IIIA with risk factors
CS IIIB-IV
Arm A
4 × COPP+ABVD
RT
Arm B
8 × BEACOPP
baseline
RT
Arm C
8 × BEACOPP
escalated
RT
RT to initial bulk and residual tumor
GHSG: HD9 Trial Design (1992 - 96)
Randomisation
Diehl et al, NEJM, 2003
BEACOPP baseline regimen
Dose D1 D2 D3 D4 D5 D6 D7 D8
D9
to
D14
Started
at D9
Blemomycin 10 mg/m2 (IV) X
Etoposide 100 mg/m2 (IV) X X X
Doxorubicin 25 mg/m2 (IV) X
Cyclophosphamide 650 mg/m2 (IV) X
Vincristine 1,4 mg/m2 (IV) [2mg max]
X
Procarbazine 100 mg/m2 (PO) X X X X X X X
Prednisone 40 mg/m2(PO) X X X X X X X X X
G-CSF 5 mg/kg/day (SC) X
BEACOPPesc regimen
Dose D1 D2 D3 D4 D5 D6 D7 D8
D9
to
D14
Started
at D9
Blemomycin 10 mg/m2 (IV) X
Etoposide 200 mg/m2 (IV) X X X
Doxorubicin 35 mg/m2 (IV) X
Cyclophosphamide 1250 mg/m2 (IV) X
Vincristine 1,4 mg/m2 (IV) [2mg max]
X
Procarbazine 100 mg/m2 (PO) X X X X X X X
Prednisone 40 mg/m2(PO) X X X X X X X X X
G-CSF 5 mg/kg/day (SC) X
261A 194 173 146 110 75 19 0469B 378 332 282 222 106 26 0466C 412 384 321 234 92 14 0
p = <.001
Pts. at Riskyears
A B C
Pro
ba
bil
ity
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
HD9 – 10-years outcome by treatment arm
BEA esc
C/ABVD
82%
64%
Engert A, JCO 2009; 27: 2548
261A 238 218 196 147 107 30 0469B 436 392 344 272 134 36 0466C 441 412 357 270 113 18 0
p = <.001
Pts. at Riskyears
A B C
Pro
ba
bil
ity
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
BEA esc 86%
C/ABVD 75%
FFTF
OS
BEACOPP vs ABVD
FFP OS
Median FU = 41 months
Federico M, JCO ,2009
Stage IIB- IV BEACOPP [esc x 4 + Baseline x 2] vs ABVD x 6
BEACOPP vs ABVD
FFP OS
Median FU = 61 months
Viviani S, NEJM 2011; 365: 203
Stage IIB- IV BEACOPP [esc x 4 + Baseline x 4] vs ABVD x 6/8
P = 0.004 P = 0.39
GELA H3-4 Trial IPS <3
Doxorubicine J1 et J15 : 25
Bleomycin J1 et J15 : 10 Vinblastine J1 et J15 : 6 DTIC J1 et J15 : 375
Bleomycin J1 10 10 Etoposide J1-3 200 100 Doxorubicine J1 35 25 Cyclophosphamide J1 1250 650 Vincristine J8 1.4 1.4 Procarbazine J1-7 100 100 Prednisone J1-14 40 40
8 x BEACOPP
R
3 1 2 5 6 7 4 8
1 2 3 4 5 7 8 6
CT scan
8 x ABVD
N =77
N =68
5y PFS* 5y OS £ 75% 92% 93% 99%
Mounier N, Ann Oncol 2014
*p= 0.008 £ p= 0.08
BEACOPPesc : Fertilité
• Hommes
90% Azoospermie après 8 x BEACOPPesc
• Femmes: Aménorrhée 4 ans après fin Chimio
Sienawski, Ann Oncol, 2008
6-8 BEACOPPesc
2 BEACOPPesc + 2 ABVD ou
4 ABVD
Behringer K, JCO, 2013
HD15
Engert A, Lancet 2012
5y FFTF: 6 Besc = 90.8% 8 Besc = 84.9% P<0.01
5y OS: 6 Besc = 96.2% 8 Besc = 91.8% P<0.01
Causes of death - N (%) BEACOPPesc x 8 (N=705) BEACOPPesc x 6 (N=711)
Total 53 (7.5) 33 (4.6)
Hodgkin lymphoma 13 (1.8) 11 (1.5)
Toxicity of chemo 15 (2.1) 6 (0.8)
2nd Neoplasia 13 (1.8) 5 (0.7)
Toxicity of salvage treatment 2 (0.3) 2 (0.3)
Other 10 (1.4) 9 (1.3)
Chimiothérapies de référence en 2014
Quel patient requière du BEACOPPesc?
5y-PFS 5y-OS
6 à 8 x ABVD 75% 90%
6 x BEACOPPesc 90% 96%
BEACOPPesc est plus éradicateur que l’ABVD, avec un meilleur contrôle de la maladie mais
sans bénéfice sur la survie démontré
International Prognostic Score
• Age > 45 y
• Male
• Albumin < 40 g/l
• Hb < 10,5 g/100ml
• WBC > 15000 /mm3
• Ly < 600 /mm3 < 8%
• Stage IV
Score FFP OS
0 (7%) 84 4 89 2
1 (22%) 77 3 90 2
2 (29%) 67 2 81 2
3 (23%) 60 3 78 3
4 (12%) 51 4 61 4
5 (7%) 42 5 56 5
Hasenclever NEJM 1998; 339: 1506
A 23 Gene expression predictor in formalin-fixed paraffin-embedded tissue
Training set Validation set
Scott D, JCO 2012; 31: 692
PFS according to IL1RA IL6 CD30s signature in stages III & IV
Score 0
Score 1-2
Score 3
P<.0001
10%
63%
27%
Casasnovas O, JCO 2007; 25: 1732
Response adapted therapy of stages III–IV Hodgkin Lymphoma based on
interim FDG-PET imaging: US intergroup S0816
• Objective: increase 2y-PFS from 70 % to 78 %
• s
ABVD x 2
5PS < 4
HL Stage III-IV
18-60 y
n = 357
TEP
BEACOPP esc x 6
n = 55 (17 %)
ABVD x 4
n = 277
5PS = 4-5
0 12 24 36 48
0
20
40
60
80
100 PET2-: ABVD
Mois
% PET2+: BEACOPPesc
Press O, Cologne 2013 – Abst T108
PFS 61%
79%
2y-PFS = 76%
Median FU = 16 months
GITIL/FIL HD0607
Positive PET2
BEACOPP esc x 4 + BEACOPP b x 4
ABVD x 2
Negative
ABVD x 5 R-BEACOPP esc x 4 + R-BEACOPP b x 4
N = 330
N = 59 (18%) N = 271 (82%)
2y-PFS 85% 61%
Gallamini A, Cologne 2013 – Abst P006 Median FU = 32 months
LYSA: AHL 2011
Standard Arm Experimental Arm
Neg / Pos
Salvage therapy
Pos Neg
PET4
PET2
Neg Pos Neg Pos Neg
Salvage therapy
BEACOPP esc x 2
BEACOPP esc x 2 BEACOPP esc x 2
BEACOPP esc x 2
R
ABVD x 2
Non inferiority of the experimental arm
ABVD x 2 BEACOPP esc x 2
BEACOPP esc x 2
GHSG: HD18
Negative PET2
BEACOPP esc x 2
BEACOPP esc x 2
BEACOPP esc x 4
Positive
End of therapy AND residual nodes > 2.5 cm:
PET positive: Rx PET negative: Follow up
BEACOPP esc x 4
PFS according to the total metabolic tumor volume at baseline (TMTV0)
TMTV0 ≤225ml
TMTV0 >225ml
P= 0.001
Kanoun S et al , EJNM 2014, 41:1735-43
PFS according to MTV0 and DSUVmaxPET0-2
N = 37 (63%)
N = 17 (29%)
N = 5 (8%)
Kanoun S et al , EJNM 2014, 41:1735-43
MAb + ABVD in advanced HL
n RC 5y-PFS Median FU
ABVD Gordon JCO 2013 404 73% 74% 77 months
ABVD Chisesi JCO 2011 126 89% 78% 86 months
ABVD Viviani NEJM 2011 166 76% 73% 61 months
R-ABVD Younes Blood 2012 78 93% 82% 68 months
R-ABVD Kasamon Blood 2012 49 81% 83% 33 months
BV-ABVD Ansell ASH 2012 / Cologne 2013
22 95% -
BV-AVD 25 96% -
Adcetris combiné à A(B)VD • 51 Hodgkin avancés (45% stade IV, 25% IPS>3, 33% Bulk)
• Aucune DLT observée (Cycle 1)
BV-ABVD BV-AVD
Inclus (n) 25 26
BV 0.6mg/kg 6 0
BV 0.9mg/kg 13 0
BV 1.2mg/kg 6 26
Tox pulmonaire gr>0/ gr≥3/gr=5 11 (44%)/ 6 (24%)/ 2 (8%) 0
Embolie pulmonaire gr≥3 3 (12%) 0
Neuropathie gr>0 18 (73%) 20 (72%)
Neutropénie fébrile gr≥3 5 (20%) 2 (8%)
ECHELON 1
Standard Arm Experimental Arm
5PS = 1-4 PET2
ABVD x 2 AVD-A x 2
R
ABVD x 4
Stage III/IV
5PS = 1-4
AVD-A x 4
Planned Accrual = 1040 pts Primary endpoint: PFS
5PS = 5
Protocol Therapy or
Salvage therapy
Drug Day 6x
BEACOPP
escalated
6x
BrECADD („experimental“)
6x
BrECAPP („standard“)
Bleomycin 8 10
Etoposide 1-3(2-4) 200 150 200
Adriamycin 1(2) 35 40 35
Cyclophosphamide 2 1250 1250 1250
Vincristine 8 1.4
Brentuximab vedotin 1 1.8 1.8
Procarbazine 1-7 (2-8) 100 100
Prednisone 1-14(2-15) 40 40
Dacarbazine 2-3 2x 250
Dexamethasone 2-5 40
Targeted BEACOPP
HD-01 trial EBMT/SFGM/GELA
• Stage IIIB-IV, < 55 y
• High risk according to Strauss criteria
– M / T >0.45
– Stage IV > 1 extranodal site
– LDH
– Inguinal node involvement
– Hb <12 (male) / 10 (female)
– Bone marrow involvement
ABVD x 4
ABVD x 4
ASCT
HD-01 trial EBMT/SFGM/GELA
8 x ABVD 4 x ABVD ASCT
n 80 80
IPS(%) 0-2
3+
39
61
44
56
5y FFS 82 75
5y OS 88 90 Median FU 50 months
Federico M, JCO 2003; 21: 2320
H97-HR GOELAMS (1997 – 2004)
• Stage IIB,III, IV; 18-60 y
• High risk:
– M / T ≥ 0.45
– Stage IV ≥ 2 extranodal site
– ≥ 5 nodal area involvement
ABVD x 4 + ASCT (BEAM)
R
VABEM x 3 + Radiotherapy 20Gy + Boost
H89
8x
ABVPP
6x
ABVPP +STNI
6x
MOPP/ABV
+STNI
8x
MOPP/ABV
n 116 96 114 92
CR (%) 99 91 95 91
10y-EFS (%) 67 69 77 71
10y-OS (%) 90 87 82 78
Ferme C, et al. Blood 2006; 107: 4636
HD12
Residual disease after chemo Initial bulk without residual disease after chemo
Borchmann P, et al. JCO 2011;29: 4234
HD15: study 2126 pts Dose density and reduction of toxicity
A B C
8 x
BEACOPP 14
( baseline)
6 x
BEACOPP
escalated
8 x
BEACOPP
escalated
Randomization
Residual tumor mass?
(>2.5 cm)
follow up
No
PET-study
PET negative:
follow up
PET positive:
RT 30 Gy 9% of all pts!
Yes
HD 15 Trial 8 vs 6 BEAesc vs 8 BEA-14
739 patients randomized and evaluable for outcome
PET after end of chemotherapy for >2,5cm rests:
Patients with rests >2,5 cm:
548 (74%) PET neg: no RT: 540 4y-PFS: 91.5%
n = 739
191 (26%) PET pos: IF-RT: 180 4y-PFS: 86.1%
PFS of patients with a residual mass >2.5cm according to PET results
Kobe C, et al. JCO 2014;32: 1776
PFS of patients with a residual mass >2.5cm according to PET results and tumor shrinkage
Kobe C, et al. JCO 2014;32: 1776
Conclusions • Pas de bénéfice démontré chez les patients en 1ère réponse:
– de la radiothérapie – de l’intensification avec autogreffe de CSH
• 6-8 x ABVD ou 6 x BEACOPPesc – BEACOPPesc est le traitement le plus éradicateur au prix d’une
toxicité immédiate et retardée significative – Pas d’éléments pronostiques simples pour cibler les patients
devant recevoir l’un ou l’autre des schémas • Risques liés à l’hématotoxicité • Fertilité
– Les stratégies TEP guidées pourraient permettre de limiter le nombre de cycles de BEACOPPesc pour les patients répondeurs précoces (>80% ?) et donc la toxicité
• BV-AVD futur challenger du BEACOPPesc ?